Original Investigation , 4 273 n ydı A , Nazan Nazan , 1 n ydı A , Mehmet Dumlu Mehmet , 3 Emet from the lower brainstem, cervical brainstem, segments and thoracic the lower from thoracic and pleural muscles, the respiration surround and continuation in the conscious surfaces, a major role and play the caliber of control (21). Autonomic of respiration the conducting pulmonary volume airways, the blood vessels, , Mucahit , 3 Cakır

6 , Zeynep , 2 E-mail: [email protected] / E-mail: kır Calık Atalay Ca This study was conducted on 20 rabbits. Experimental SAH was induced by injecting the by induced homologous blood into SAH was Experimental conducted on 20 rabbits. study was This

INTRODUCTION Çalışma 20 tavşanda gerçekleştirildi. Sisterna magnaya homolog kan enjeksiyonuyla deneysel SAK oluşturuldu. Deney oluşturuldu. SAK kanhomolog deneysel enjeksiyonuyla gerçekleştirildi. magnaya Sisterna tavşanda 20 Çalışma Hasar, Solunum, Tavşan, Subaraknoid kanama, Vagal sinir Vagal Subaraknoid kanama, Tavşan, Solunum, Hasar,

: : , Canan Canan , 1 , Muhammed Muhammed , 5 r If vagal nerves are lesioned, the muscles of respiration are paralyzed and respiratory reflexes are disrupted. That the ischemic That disrupted. are and respiratory reflexes paralyzed are the muscles of respiration If nerves vagal lesioned, are Accepted: 11.02.2014 / Accepted: 03.12.2013 Received: DOI: 10.5137/1019-5149.JTN.9964-13.1 Kontrol grubunda ölçüldüğü şekildeölçüldüğü grubunda şeklindeydi.normaldk 30±6 hızı solunum indüklenmişSAK Kontrol hızlarısolunum grupta , Respiration, Rabbit, , Vagal Vagal Rabbit, hemorrhage, Respiration, Injury, Subarachnoid

GEREÇLER Cakır : and Methods: Normal respiration rate, as measured in the control group, was 30±6 bpm. In the SAH-induced group, respiration rates were were rates respiration Inbpm. group, 30±6 was SAH-induced the group, control the in measured as rate, Normalrespiration LER SÖZCÜK

ve

AR Vagal sinirlerde lezyon oluşursa, solunum kasları felce uğrar ve solunum refleksleri bozulur. SAK’nın oluşturduğu iskemik ve mekanikve iskemik oluşturduğu SAK’nın bozulur. refleksleri solunum lezyonve sinirlerde kaslarısolunum uğrar oluşursa, felce Vagal AR Subaraknoid kanamada (SAK) bozukluklarının solunum sinir kökü bir ilişki şiddetiyle vagal hasarı arasında inceledik. olup olmadığını Onde ords: We examined whether there is a relationship between vagal nerve root injury and the severity of respiration disorders associated with nerve vagal associated between injury disorders root is a relationship whether there and the severity examined of respiration We GUL AÇ: l terIal Ataturk University, School of Medicine, Department of Neurosurgery, Erzurum, Turkey Erzurum, Department of Neurosurgery, of Medicine, School University, Ataturk Turkey Department of Anesthesiology Erzurum, of Medicine, School and Reanimation, University, Ataturk Turkey Erzurum, Department of Emergency Medicine, of Medicine, School University, Ataturk Turkey Department Erzurum, of Psychiatry, of Medicine, School University, Ataturk Turkey Istanbul, Department of Neurosurgery, Avrasya Hospital, Turkey Erzurum, Department of Pathology, of Medicine, School University, Ataturk Arif 1 2 3 4 5 6 Murteza M on: onclusI ÖNTEM Keyw ANAHT C SONUÇ: BUL Results: A Y Ma AIm: and mechanical factors created by SAH cause vagal nerve root injury and respiration disorders may be inevitable and fatal. be inevitable and fatal. nerve may SAH cause vagal injury disorders by root and mechanical factors and respiration created faktörlerin vagal sinir kök hasarı ve solunum bozuklukları oluşturması kaçınılmaz ve ölümcül olabilir. solunum bozuklukları sinir kök hasarıfaktörlerin vagal ve oluşturması kaçınılmaz ölümcül olabilir. ve initially 20±4 bpm, increasing to 40±9/min approximately ten hours later, with severe tachypneic and apneic variation. In histopathological In and apneic variation. histopathological tachypneic with severe hours later, ten 40±9/min approximately to initially 20±4 bpm, increasing densityin 22250±3500 was whereas animals, sham and density nerves vagal of control both 28500±5500 in axon was examinations, than in the six dead animals nerves of vagal greater degeneration was severity of axonal The survivors and 16450±2750 in dead SAH animals. in the survivors. şiddetli takipneikbaşlangıçta sonrasında apneik varyasyonla 20±4 dk iken, on saat incelemelerde 40±9/dk değerine ve yükseldi. Histopatolojik hem taklithem kontrol sinirlerin (sham) deneklerindevagal SAK deneklerinde akson yoğunluğu ölü 28500±5500 iken yaşayan 22250±3500 ve daha fazlaydı. yaşayanlardan şiddeti 6 ölü denekte aksonal dejenerasyonun sinirlerde Vagal SAK deneklerinde 16450±2750 bulundu. sırasında günlük olarak elektrokardiyografi ve solunum ritimleri ölçümü yapıldı. Deneyden sonra, vagal sinirlerin vagal arteriyel sonra, solunum ritimleri Deneyden ölçümü yapıldı. nervorumlarındaki ve elektrokardiyografi günlük olarak sırasında analiz edildi. olarak istatistiksel solunum düzensizlikleri sinir dejenerasyonları vagal ve Tüm değişiklikler aksonal hasar incelendi. varsa ve cisterna magna. During the experiment, electrocardiography and respiratory rhythms were measured daily. After the experiment, any axonal axonal any the experiment, After daily. measured were and respiratory rhythms During electrocardiography magna. the experiment, cisterna injury the arterial nerve or changes to and vagal respiratory irregularities All degenerations nervorums examined. nerves the vagal of were analyzed. statistically were Respiration can be defined as a process of gas exchange in the exchange of gas can be defined as a process Respiration lungs via inspiratory and expiratory (7, 21). Respiratory drives nervous innervated and autonomic somatic are by organs sensitive-motor somatic The nerves arise (24). systems Corresponding Author: Murteza Subaraknoid Kanamada Solunum Bozuklukları Oluşmasında Vagal Vagal Kanamada Oluşmasında Bozuklukları Solunum Subaraknoid Rolü Hasarının Sinir Kökü The Role of Vagal NerveVagal Injury Root Respiration on Role of The Disturbancesin Subarachnoid Hemorrhage Turk Neurosurg 2015, Vol: 25, No: 2, 273-278 Vol: 2015, Neurosurg Turk ÖZ subarachnoid hemorrhagesubarachnoid (SAH). ABSTRACT Cakir M. et al: Vagal Nerve Root Injury in Subarachnoid Hemorrhage

of respiratory units, the activity of bronchial glands and Xylazine HCL, 30 mg/1.5 mL; and distilled water, 1 mL) was respiration reflexes. The vagal nerve is the principle neural subcutaneously injected immediately before surgery. All pathway that interconnects the brainstem and the lungs. It animals were monitored for electrocardiographic changes, is involved in maintaining the rhythm of central respiration, respiration patterns, and blood oxygen concentrations and regulation of the pulmonary vasculature, airways and during the procedures. All parameters were recorded by Sony pulmonary secretion (8). Activation of the pulmonary stretch camera and were analyzed by physicians who were blinded receptors by lung inflation or vagal stimulation evokes the to study. During the operation, 0.1 mL/kg of anesthetic Hering-Breuer reflex, which is characterized by inspiratory combination was used as required. For the SAH group, 0.75 mL inhibition and expiratory prolongation (13). Stimulation of of autologous blood was taken from the auricular artery and the vagal nerve can cause bronchoconstriction, respiration injected into the cisterna magna via a 22-gauge hypodermic rhythm disorders and apneustic attacks (18). When respiration needle over approximately one minute. For the SHAM group, units are deformed by chemical, pathophysiologic or 0.75 mL of isotonic saline solution was injected instead of mechanical factors, these neural networks initiate the Hering- blood. Six of the ten rabbits subjected to experimental SAH Breuer reflex and affect the pattern of breathing (16,19). So, died within the first week post-surgery and the surviving four ischemic vagal discharges resembling vagal stimulation were followed for 20 days without any medical treatment and may be considered a triggering factor in apneustic attacks then sacrificed. At that point, the lungs and all vagal nerves at the beginning of subarachnoid hemorrhage (SAH). The just over the jugular foramen were removed for histology immunoregulatory role of the vagal nerve on the lungs may examination. Tissues were kept in a 10% formalin solution for be damaged secondary to vagal , and respiratory 7 days, following which 1 µm tissue sections were taken and rhythm may be disrupted due to lung inflammation (9). stained with S-100. For the purpose of this study, body necrosis and degenerated axon numbers were the Vagal nerve injury can cause laryngopharyngeal muscle pa- injury criteria of vagal nerves. ralysis, tracheobronchial distortions, reflex vagal bradycardia To estimate the total number of of vagal nerves, the and bradypnea (22). In late phase SAH, irreversible axonal fractionation technique was used after the cross-sections injury may mimic a blockade of the vagal nerves. The Hering- of the vagal nerves were obtained according to the basic Breuer reflex may be abolished during acutely developed ce- sampling procedure and stereological principles described rebral and restored by recovery of ischemic cerebral by Gundersen (10). Axon density of the vagal nerve was processes (1, 20). It is well known that axon density of vagal estimated using an unbiased counting frame of known size. nerves plays an important role in their activities (14). Also, The microscope used had a two attachments; a camera and density of autonomic ganglions strongly affects au- was and a platform with two dial indicators and two arms for tonomic functions (14). So, axon density of vagal nerves may mounting the microscope stage. The two dial indicators (5 µm be an important factor in the regulation of respiration, and resolution) mounted to the microscope measured movement reduced neuron density due to SAH may cause respiration in the x and y planes of the stage. The vagal nerve images disorders and even arrest. In the presented study, it is demon- and measurements obtained were recorded by the camera strated that SAH causes not only cerebral ischemic insult, but and uploaded to a computer and the numbers of living and also brain stem and cranial nerve . We hypothesized degenerated of the vagal nerve of all animals were that ischemic vagal nerve root injury is an important factor in counted. the development of respiratory arrhythmia; a novel concept not previously studied. In order to estimate respiration capacities and depth, respiration-time curves generated by computer were MATERIAL and METHODS overlaid onto minisquare pointed papers in order to facilitate This study was conducted at the Medical Experimental calculations (See Figure 3 for an example). The height of the Research Center, Ataturk University. The Ethical Committee curve from the basal line to the apical points was accepted of Ataturk University approved the study protocol. All as respiration depth and the surface area under the curve procedures were performed in accordance with the National was accepted as respiration capacity per respiration cyclus Institute of Health Principles of Laboratory Animal Care. A recorded over a period of two seconds. Then, these values total of twenty hybrid rabbits aged two years and weighing were multiplied by 30 in order to calculate mean values per 3.5 ± 025 kg were used. Four rabbits (n=4) were determined minute. as a control group and were not subjected to surgery. The Numbers of degenerated vagal nerve root axons, respiration remaining animals (n=16) were divided into two groups; SAH depths and respiration capacity values were compared group subjected to artificial subarachnoid hemorrhage (n=10) between the three groups using the Mann-Whitney U test. and a SHAM group subjected to a similar surgical procedure RESULTS without inducing SAH (n=6). Animals were fasted for 6 hours prior to surgery. A balanced injectable anesthesia was used Six of the SAH-induced animals and one of the SHAM group for reducing pain and mortality. After inducing anesthesia animals died within the first 7 days post-surgery due to with isoflurane administered via a facemask, 0.2 mL/kg of respiration arrest, and the remaining animals (n=4 of SAH; n=3 the anesthetic combination (Ketamine HCL, 150 mg/1.5 mL; of SHAM) were followed for a total of 20 days post-surgery.

274 Turk Neurosurg 2015, Vol: 25, No: 2, 273-278 Cakir M. et al: Vagal Nerve Root Injury in Subarachnoid Hemorrhage

Clinically, signs of meningeal irritation, unconsciousness, considered evidence of axonal injury. These changes in the convulsive attacks, fever, apnea, cardiac arrhythmia and vagal nerves were observed more often in animals that died breath disturbances were observed frequently in premortal than in those that lived for the 20 days of observation (Figures periods of all of the animals who expired within the first week 3, 4). Normal respiration rate was 30±6 bpm. Stereological post-surgery and three of the animals who survived for the examinations revealed a normal axon density of vagal nerves full 20 days. of 28500±5500 in both the normal control animals and the SHAM group, whereas mean axon density was 22250±3500 In normal animals, cardiac pulse was 250±30 bpm; breath in survivors and 16450±2750 in dead SAH animals. The pulse was 30±7 bpm and blood oxygen concentration was severity of axonal degeneration of vagal nerves was greater 95±5%. In the early stages of induced SAH, cardiac rhythm in the dead SAH animals (16750±4750) than in the survivors decreased to 140±40 bpm; breath pulse to 15±5 bpm and (5700±750) (p<0.0001). Respiration capacity and depth blood oxygen concentration to 70±10%. A considerable are summarized in Figure 5. There was a linear relationship electrocardiographic change was observed as ST depression, between the respiration variables and the degree of axonal ventricular extrasystoles, bigeminal pulses, QRS separation injury of vagal nerves. and fibrillations. However, in the late stages of mortal SAH, cardiac pulse increased to 330±30 bpm. Initially, respiration With regard to the respiration parameters and histopatho- rates were 20±4 bpm; about ten hours later respiration logical changes of the vagal nerves observed, degenerated increased to 40±9 bpm with severe tachypneic and apneic axons were more prominent in animals that developed high variation. In the analyses of respiration parameters, decreases in respiration frequency (bradypnea) (15±5) and increases respiration amplitude (30%) were observed during the first few hours following induced SAH. After the first few hours, increased respiration frequency (tachypnea) and decreased respiration amplitude (30±8%), reduced inspiration and extended expiration time, apnea-tachypnea attack, diaphragmatic breath and, finally, respiration arrest were observed. Figure 1 illustrates the macroscopic appearance of the brain of a deceased SAH animal; Figure 2 illustrates normal vagal nerve roots. In histopathological examination of the vagal nerve, axonal and periaxonal thinning, axonal loss and expanded interaxonal space were accepted as axonal degeneration criteria. Also, in animals that died prior to the end of the 20- day observation period, decreased darkening points were

Figure 2: Vagal nerve roots just over the jugular foramen (LM, S-100, x 20).

Figure 3: Transverse section of a visceromotor branch of vagal nerve root at the brainstem level of a normal rabbit (NA-Normal Figure 1: Basal view of a brain with SAH created animal. axon of vagal nerve) (LM, S-100, x 40).

Turk Neurosurg 2015, Vol: 25, No: 2, 273-278 275 Cakir M. et al: Vagal Nerve Root Injury in Subarachnoid Hemorrhage

frequency tachycardia than those with low frequency tachy- upper five thoracic sympathetic ganglia. Preganglionic cardia. Also, animals that displayed respiration irregularity parasympathetic fibers travel through the pulmonary and arrest had more mechanical lesions of nerve roots and plexus and terminate in ganglia situated along the course of degenerated axons in their vagal nerves. conducting airways. The ganglia are composed of excitatory cholinergic neurons and inhibitory noradrenergic neurons. DISCUSSION Parasympathetic innervation seems to predominate over In fatal SAH, respiration muscles are paralyzed and breathing sympathetic innervation (3). Sensory afferent fibers are also reflexes are broken down due to ischemic insult of vagal present in the autonomic and somatic nerve plexuses. The nerve and other lower cranial and upper cervical nerve somatic sensitive-motor nerves surround the respiration injuries, increased intracranial pressure and mechanical muscles, pleural and thoracic surfaces. The parasympathetic consequences of brain stem herniation (11). Autonomic system plays a major role in the continuation of spontaneous innervation of respiratory organs is sustained by branches respiration. Sympathetic nerve fibers lie within the walls of from the vagal nerves and the lower four cervical and pulmonary artery branches, but the parasympathetic nerves associated with pulmonary circulation is less well known and probably less extensive (12). We investigated the role of the injured vagal nerve on respiration rhythm disorders associated with SAH. We showed that axonal injury occurred in the vagal nerves on radicular levels. All autonomic and somatic nerves control the caliber of the conducting airways and pulmonary blood vessels, the volume of respiratory units, the activity of bronchial glands and respiration reflexes. Pulmonary-based reflexes are maintained primarily by vagal nerves (4). Together, the vagal and spinal sensory fibers and sympathetic fibers form the pulmonary plexus, and these regulate lung functions via microganglia. Microganglia are associated with the plexus and the peripheral ends of the vagal nerve branches in the larynx, epiglottis, trachea, bronchi, blood vessels, smooth muscles of airways, the submucosa and the secretory cells (24). The vagal nerve is the principle neural pathway that interconnects the Figure 4: Transverse section of a thinned visceromotor branch brainstem and the lungs. The vagal nerve is involved in both of vagal nerve root at the brainstem level of a dead rabbit (NA- central respiration rhythm and the regulation of pulmonary Normal axon of vagal nerve) (LM, S-100, x 40).

Figure 5: Schematic representation of respiration- time curve showing that the respiration depths (d) and inspiration capacities of all groups (I1,2,3,…n). The height of the curves from basal line to the apical points accepted as respiration depth and the surface covered by curve and basal line accepted as respiration capacity per respiration cycles recorded during two seconds. Then, these values multiplied with 30 for the calculation of the mean values of per minutes. The A curve belong to normal animals, The B curve belong to survivors and the C curve belong to dead animals.

276 Turk Neurosurg 2015, Vol: 25, No: 2, 273-278 Cakir M. et al: Vagal Nerve Root Injury in Subarachnoid Hemorrhage

vasculature, airways and pulmonary secretion (8). The reflex vagal bradycardia and bradypnea. This requires immunoregulatory role of the vagal nerve on the lungs may activation of cardiac vagal preganglionic neurons, which be damaged secondary to vagal nerve injury, and respiration exhibit postinspiratory discharge (22). rhythm may be disordered because of lung inflammation (9). In subarachnoid hemorrhage, the arteries of the vagal nerve Activation of the pulmonary stretch receptors by lung roots are affected by vasospasm-generated mechanisms. inflation or vagal stimulation evokes the Hering-Breuer reflex, Vagal reactivity predominantly regulates the resistance which is characterized by inspiratory inhibition and expiratory of peripheral airways during inspiration (6). The Hering- prolongation (13). Long duration stimulation of the vagus Breuer reflex may be abolished during acutely developed nerve produced a classic Hering Breuer reflex characterized cerebral ischemia and restored by recovery of ischemic by the inhibition of inspiration and the facilitation of cerebral processes (1, 20). In the present study, it is shown inspiration. High frequency stimulation of the central end that SAH causes not only cerebral ischemic insult, but also of the vagus nerve induces a shortening of the inspiratory brainstem and cranial nerve injuries. We hypothesized that phase and lengthening of the expiratory phase (25). Vagal ischemic vagal nerve root injury is an important factor in the nerve stimulation also induces bronchoconstriction (12). development of respiratory arrhythmia. We demonstrated Another important cause of breath disability associated that subarachnoid hemorrhage may result in histopathologic with the beginning of SAH is bronchoconstriction due to ischemic changes, an observation not previously reported. ischemic vagal discharge. Bilateral vagus nerve stimulation We have got some limitations. First, the devices such as ECG for 30 seconds causes bronchoconstriction and respiration and monitor we used were designed for human patients. rhythm disorders characterized by apneustic attacks (18). So, Thus, although we have used them in the setting of new ischemic vagal discharge resembling vagal stimulation may borns, there may be measurement mistakes due to mismatch. be considered as a triggering factor in apneustic attacks at Second, we did not evaluate injury in respect to the duration the beginning of SAH. and severity of SAH. Third, this is an animal study, thus the The centrally generated respiratory rhythm is under strong results cannot be generalized to human patient. It is better to modulation by peripheral information, such as that from the conduct a study evaluating the effect of SAH on vagal nerves slowly adapting pulmonary stretch receptors conveyed via in postmortem SAH patients. the vagus nerve (23). Irritant receptors are rapidly adapting CONCLUSION receptors and localized mainly in extrapulmonary airways. They are stimulated by irritative mechanical and chemical it is well known that the vagal nerves play many important stimuli that produce bronchospasm (15). Irritant receptors role on the continuation of respiration, such as regulation play a major role in breath rhythm regulation in critical of airways and pulmonary vessel resistance, pulmonary situations by causing bronchial and tracheal constriction, pressure, the Hering-Breuer reflex, blood pH, respiration and rapid shallow breathing, and a decrease in the heart rate heart rhythm coordination, lung metabolism and immunity. (5). All afferent nerve fibers to the In subarachnoid hemorrhage, vagal nerve root injury causes from receptors in the lungs and airways travel in the vagus corruption of efferent and afferent vagal reflexes, which leads nerve. Most of the afferent fibers innervating the lungs are to a breakdown in the regulation of respiration mechanisms. conveyed via vagal nerves. Impulses of chemoreceptors are Ultimately, these pathologic processes cause respiration conveyed by glossopharyngeal and vagal nerve fibers to the arrest and death. respiration centers (17). Skeletal muscle proprioceptors of REFERENCES somatosensitive nerves play a major role in the conscious continuation of respiration (21). When respiration units are 1. Aydin MD, Ozkan U, Gündoğdu C, Onder A: Protective effect deformed by chemical, pathophysiologic or mechanical of posterior cerebral circulation on carotid body ischemia. factors, these neural networks initiate the Hering-Breuer Acta Neurochir 144:369-372, 2002 reflex and affect the pattern of breathing (16, 19). 2. Bouairi E, Neff R, Evans C, Gold A, Andresen MC, Mendelowitz D: Respiratory sinus arrhythmia in freely moving and Blockade of vagal nerves by capsaicin greatly reduces the anesthetized rats. J Appl Physiol 97:1431-1436, 2004 frequency of spontaneous augmented breaths. Carotid sinus diminishes both the frequency and amplitude of 3. Cohhen MI: Neurogenesis of respiratory rhythm in the spontaneous augmented breaths (17). During the late phase of mammal. Physiol Rev 59:1105-1173, 1979 SAH, irreversible axonal injury of the vagal nerve may mimic a 4. Crapo JD, Barry BE, Gehr P, Bachofen M, Weibel ER: Cell blockade of vagal nerves. Respiratory sinus arrhythmia occurs number and cell characteristics of the normal human lung. mainly due to inhibition of cardioinhibitory parasympathetic Am Rev Respir Dis 126:332-337, 1982 cardiac vagal neurons during inspiration (2). Ryan et al. (22) 5. Dehkordi O, Rose JE, Balan KV, Kc P, Millis RM, Jayam- showed that vagal nerve injury causes laryngopharyngeal Trouth A: Neuroanatomical relationships of substance muscle paralyses and tracheobronchial distortions. Distortion P-immunoreactive intrapulmonary C-fibers and nicotinic of the upper airway by negative transmural pressure causes cholinergic receptors. J Neurosci Res 87:1670-1678, 2009

Turk Neurosurg 2015, Vol: 25, No: 2, 273-278 277 Cakir M. et al: Vagal Nerve Root Injury in Subarachnoid Hemorrhage

6. Fuller SD, Freed AN: Partitioning of pulmonary function 16. Matsumoto S: Effects of vagal stimulation on slowly adapting in rabbits during cholinergic stimulation. J Appl Physiol pulmonary stretch receptors and lung mechanics in 78:1242-1249, 1995 anesthetized rabbits. Lung 174:333-344, 1996 7. Gail DB, Lenfant CJM: Cells of the lung: Biology and clinical 17. Matsumoto S, Takeda M, Saiki C, Takahashi T, Ojima K: implications. Am Rev Respir Dis 127:366-387, 1983 Effects of vagal and carotid chemoreceptor afferents on the 8. Gaspari RJ, Paydarfar D: Respiratory failure induced by acute frequency and pattern of spontaneous augmented breaths organophosphate poisoning in rats: Effects of vagotomy. in rabbits. Lung 175:175-186, 1997 Neurotoxicology 30:298-304, 2009 18. Matsumoto S: Low frequency-dependent mechanism of the 9. Goehler LE, Erisir A, Gaykema RP: Neural-immune interface M2 receptor function on vagally mediated bronchoconstric- in the rat area postrema. Neuroscience 140:1415-1434, 2006 tion in rabbits in vivo. Life Sci 65:103-112, 1999 10. Gundersen HJ, Bendtsen TF, Korbo L, Marcussen N, Møller A, 19. Monier A, Burnet H, Jammes Y: Hypoxemia does not affect the Nielsen K, Nyengaard JR, Pakkenberg B, Sørensen FB, Vesterby strength of the inspiration-inhibiting Breuer-Hering reflex. A: Some new, simple and efficient stereological methods Neurosci Lett 197:129-132, 1995 and their use in pathological research and diagnosis. APMIS 20. Pluta R, Romaniuk JR: Recovery of breathing pattern after 15 96:379–394, 1988 min of cerebral ischemia in rabbits. J Appl Physiol 69:1676- 11. Hawkins TD, Sims C, Hanka R: Subarachnoid haemorrhage 1681, 1990 of unkown cause: a long-term follow-up. J Neurol Neurosurg 21. Polgar G, Weng TR: The functional development of respiratory Psychiatry 52:230-235, 1989 system from the period of gestation to adulthood. Am Rev 12. Lama A, Delpierre S, Jammes Y: The effects of electrical Respir Dis 120:625-695, 1979 stimulation of myelinated and non-myelinated vagal motor 22. Ryan S, McNicholas WT, O’Regan RG, Nolan P: Effect of upper fibres on airway tone in the rabbit and the cat. Respir Physiol airway negative pressure and lung inflation on laryngeal 74:265-274, 1988 motor unit activity in rabbit. J Appl Physiol 94:1307-1316, 13. Li Y, Song G, Cao Y, Wang H, Wang G, Yu S, Zhang H: Modulation 2003 of the Hering-Breuer reflex by raphe pallidus in rabbits. 23. Takano K, Kato F: Inspiration-promoting vagal reflex in Neurosci Lett 397:259-262, 2006 anaesthetized rabbits after rostral dorsolateral pons lesions. 14. Licursi de Alcântara AC, Salgado HC, Sassoli Fazan VP: J Physiol 550:973-983, 2003 Morphology and morphometry of the vagus nerve in male 24. Taylor SM, Pare PD, Schellenberg RR: Cholinergic and and female spontaneously hypertensive rats. Brain Res nonadrenergic mechanisms in human and guinea-pig 1197:170-180, 2008 airways. J Appl Physiol 56:958-965, 1984 15. Matsumoto S: The activities of lung stretch and irritant 25. Wang GM, Song G, Zhang HP: Phenomenon of non-associative receptors during cough. Neurosci Lett 19:125-129, 1988 learning in Hering-Breuer reflex simulated by electrical vagal stimulation in rabbits. Sheng Li Xue Bao 57:511-516, 2005

278 Turk Neurosurg 2015, Vol: 25, No: 2, 273-278